Introduction
Rotator cuff calcific tendinopathy (RCCT) involves the deposition of calcium within the rotator cuff tendons of the shoulder, most commonly within the supraspinatus tendon.1 The observation of calcific deposits is a common radiographic and ultrasonographic finding.2 It has been observed in 7.8%–13.6% of people not reporting shoulder symptoms2 and in 33.3%–42.5% of symptomatic people.2 The prevalence of RCCT increases around the third and fourth decades and peaks during the fifth decade.3 Women are more commonly affected than men.3 The role of biomechanical factors in the development of RCCT is still under debate.4 In particular, there is uncertainty regarding whether arm dominance, specific shoulder positions and repetitive high-speed work movements contribute to this clinical condition in a similar way that occurs with non-calcific rotator cuff tendinopathy.5 6 Several risk factors have been associated with the development of this condition such as obesity, diabetes, metabolic syndrome, thyroid alterations and hypertension.7
RCCT is often associated with tenderness near the greater tuberosity of the humerus, nocturnal discomfort and reduced shoulder range of motion.8–10 Three stages of the condition have been defined (pre calcific, calcific and post calcific), with symptoms thought to peak during the calcium resorption that occurs in the latter phases of the calcific stage, resulting in a self-limiting pain.11 The pathoaetiology of RCCT remains equivocal and may be self-limiting. No study has yet determined its natural history, nor if there is a spontaneous resolution of symptoms at any point of its course.
The management of RCCT is mainly conservative. Simpson et al12 reported substantial heterogeneity, compounded by poor methodological quality, in the studies investigating the effectiveness of non-surgical interventions for RCCT. Therefore, no strong evidence in favour of any non-surgical intervention was identified.12 High-energy extracorporeal shockwave therapy (ESWT) appears to be a more effective non-surgical intervention when compared with placebo for improving shoulder function in the first 6 months after completing the intervention. In this review, ultrasound-guided percutaneous irrigation of calcific tendinopathy (US-PICT) demonstrated superiority to ESWT for long-term pain and calcification reduction12; however, US-PICT has yet to be adequately compared with placebo.12
Interestingly, in the review mentioned above,12 the lack of evidence about the effectiveness of exercise therapy (ET) for this clinical condition was emphasised. ET is considered the mainstay treatment for people with rotator cuff tendinopathy13 and has demonstrated similar long-term outcomes to surgery regarding pain and function in this population.14 Recently, a holistic rehabilitation programme called Shape-Up-My-Shoulder (SUMS) for people with Rotator Cuff Related Shoulder Pain (RCRSP) has been presented.15 SUMS is a multistage programme that involves early-stage rehabilitation exercises including Shoulder Symptom Modification Procedures (SSMP)16 progressing to isometric, eccentric and heavy slow resistance (HSR) exercises and a final stage comprising functional exercises.
In addition, no study has compared non-surgical management of RCCT with a no treatment (ie, wait-and-see group) group yet. Therefore, the natural history of RCCT is currently unknown.12 Previous studies have included wait-and-see groups receiving educational interventions or brief advice.17 However, it is not possible to establish the natural history of RCCT if any educational or briefly advice intervention is applied, since these types of interventions might have a potential therapeutic effect on their own.
Objectives
The main objective of this study is to examine the effectiveness of an ET programme compared with ESWT, US-PICT and a wait-and-see group in individuals with RCCT. The secondary objective of this study is to report preliminary data about the natural history of RCCT based on the observation of the wait-and-see group.
As the effectiveness of exercise has been shown to be similar to other forms of treatment (eg, surgery) in people with RCRSP, we hypothesise that ET will be as effective as ESWT and US-PICT in the short-term and long term in terms of pain and function in people with RCCT.13 18–24 Additionally, we hypothesise that the wait-and-see group will also report some improvements in the outcomes measured during the follow-up assessments due to the self-limited nature of RCCT.1 10 25 26
Methods and analysis
Study design
A four-arm randomised single-blinded controlled clinical trial including concealment to group allocation and intention-to-treat analysis will be performed to evaluate the effectiveness of three different interventions (ET, ESWT and US-PICT) and compared them with no-treatment for people with RCCT. The planned starting and ending dates for this study are May 2023 and May 2025, respectively. Figure 1 details the flow of the investigation.
Flow chart of study process. ESWT, extracorporeal shockwave therapy; ROM, range of motion; SPADI, Shoulder Pain and Disability Index; SUMS, Shape-Up-My-Shoulder Protocol; US-PICT, ultrasound-guided percutaneous irrigation of calcific tendinopathy; VAS, Visual Analogue Scale.
Participants
Recruitment
The recruitment will take place at Lluís Alcanyís Hospital and La Fe Hospital, both located in Valencia, Spain. Patients with RCCT attending to the orthopaedic surgery unit and the radiology unit, who are on the waiting list to receive treatment, will be assessed for eligibility by an orthopaedic surgeon. Screening and enrolment will continue until the target number of 116 participants is achieved.
Eligibility criteria
Inclusion criteria: people aged from 30 to 75 years old; calcification deposit in the rotator cuff confirmed by diagnostic imaging (ultrasound, MRI or X-ray); and presence of at least moderate Shoulder Pain and Disability Index (SPADI>20).27
Exclusion criteria: currently receiving physiotherapy or ESWT for RCCT or having received any previous treatments (eg, injections, ESWT, US-PICT, surgery, exercise, etc) in the previous year; other shoulder disorders or trauma (eg, fractures, dislocations, traumatic rotator cuff tears, frozen shoulder or shoulder instability); known allergy to any of the pharmacological products used in the study; taking oral anticoagulants; taking oral steroid within the 6 months prior to participation in the study; cancer, systemic disease, pregnancy or infection, glaucoma, unstable blood pressure, unstable diabetes; and neck pain.
Informed consent and baseline assessment
All the information pertaining to the study and the data protection system will be explained verbally and provided in a participant information document. Eligible individuals will be asked to sign an informed consent form (online supplemental material 1).
Supplemental material
Thereafter, baseline measurements (table 1) will be collected. After the baseline assessment, participants will be randomised into one of the four groups.
Participant timeline
Randomisation, allocation concealment and blinding
Participants will be block randomised using a centralised computer-generated random number generator (www.random.org) into one of the four groups (1:1:1:1). To ensure that participants have an equal chance to receive each intervention or control, randomisation will be stratified by gender and age using a variable block size (ranging from 4 to 8).
Group allocation will be concealed from the assessor using sequentially numbered opaque envelopes. They will be opened by the participant, in the presence of the recruitment team and not in the presence of the assessor.
The principal evaluator in charge of measuring primary and secondary outcomes will be blinded to participants’ group allocation, data collection and analysis. Moreover, the radiologist in charge of measuring imaging outcomes will also be blinded to the intervention group. Participants will not be blinded due to the impossibility to conceal the interventions, since their nature is very different between them. Medical practitioners and physiotherapists performing the interventions will not be blinded, since they need to know which intervention is going to be applied in each case.
Interventions
Exercise therapy
This group will receive the SUMS protocol,15 and it will be led by a physiotherapist trained in exercise physiology.
Stage I: early-stage rehabilitation exercises and SSMP
This stage typically lasts 1–2 weeks, although this is individualised according to the participant’s symptom level and ability to progress. It includes the implementation of SSMP16 and early-stage rehabilitation exercises (ie, breathing and relaxation exercises, ball rolling exercises, hand gripping exercises, mental imagery and contralateral side exercises). If the patient’s symptoms do not clinically improve with SSMP (ie, a meaningful subjective reduction of symptoms), the clinician should move on to another early-stage rehabilitation technique. If improvement is still not achieved with these exercises or techniques, the next stage in the #SUMS protocol is to move on to isometric contractions.15
Isometric contractions
Isometric contractions will serve as a bridge between stage I and stage II. The most provocative direction of shoulder movement will be chosen. Then the clinician will ask first to perform a maximal isometric contraction on the patient’s asymptomatic side (if possible). This may help patients understand how to perform the exercise and a maximal isometric contraction in the affected side. After that, the same movement will be performed on the symptomatic side as close to the most provocative position as possible. The patient will be asked to perform an isometric contraction at 50% of their maximal force, hold for 3 s, rest 3 s and repeat four times.28
Stage II: eccentric and HSR exercises
The second stage starts progressing to slow eccentric contractions29 and then heavy slow-release contractions30 (ie, eccentric and concentric). These are done in the most painful directions of shoulder movement. This is an individualised programme, but people with RCRSP often refer to pain during abduction and external rotation. Therefore, if these movements are symptomatic, they take priority. Patients start with an eccentric contraction on the symptomatic side with no external load, focusing on mental imagery of a ‘substantial’ external load. These exercises are performed every other day, preferably at the end of the day, with no additional loading added after the exercises. Patients are encouraged to use a metronome set to 60 beats per minute to control the speed. During the eccentric contraction, patients should count five beats (5 s) and then passively return to the starting point. One progression is to gradually increase the load, aiming for three sets of five repetitions.29
The final part of stage II involves progressing from eccentric only to eccentric and concentric contractions, using the same number of repetitions and sets as for the eccentric stage of the programme, but introducing an exercise programme known as HSR.30 Concentric contractions are now introduced, while maintaining the same exercise position used during the eccentric-only programme. The metronome is still used, with each direction taking around 3 s. Starting at 70% of the repetition maximum (RM) and performing one set of five repetitions. Then, progressing to 85% of RM, and performing three sets of three repetitions, each with a tempo of 3 s.30
Pain is permitted during exercise, but there should be no increase in night pain or pain the following day. If pain reaches these levels, the exercise must be adjusted accordingly such as by reducing weight, the number of repetitions, sets, etc.
There is an overlap between the stages, and when the patient is able, typically around weeks 4–6, he or she progresses to the final stage. Progression or regression within the programme is based on the patient’s response.
Stage III: functional program
This is the final stage of the SUMS programme, where the main objective is returning the patient to function. This stage typically starts in week 5 or 6 and continues through week 12. Stage III involves a range of activities, including pushing, pulling, throwing, lifting, carrying and precision (sensorimotor control) exercises, aligning with the shoulder’s role in normal function. By the end of the programme, participants will, on average, be performing three to five exercises at home each day. These exercises will vary on alternate days and will progress in terms of complexity, weight, speed and ‘chaos’. Figure 2 details a progression for a pushing programme. The other functional activities follow similar graduated progressions.
Pushing programme progression. Used with permission from Lewis and Fernández-de-las-Penas.15
High energy ESWT
The ESWT group will receive high energy ESWT following the recommendations of a recent systematic review12 and Ioppolo et al,31 always administered by the same experienced physiotherapist with 10 years of expertise in applying this technique. The equipment used will be a focal shock wave device provided by Storz Medical. ESWT will be applied on the most tender point located by palpation in the supraspinatus tendon insertion area. Parameters will be adjusted at 1500 impulses per session without anaesthesia, a frequency of 4 Hz and an intensity between 0.15 and 0.30 mJ/mm2, depending on patient pain tolerance.12 A total of four treatment sessions (one session per week, each lasting 20 min) with 1 week of rest between sessions will be implemented. The patient’s position during the treatment will be seated with shoulder hyperextension and internal rotation with the hand placed below the contralateral glute with the palm touching the table.32
Ultrasound-guided percutaneous irrigation of calcific tendinopathy (US-PICT)
This intervention will be performed by an interventional radiologist with 8 years of experience performing US-PICT. The intervention will consist of two sessions with 3 months of rest between sessions. The shoulder will be placed in hyperextension and internal rotation with the hand behind the back.12 One 20 mL syringe with saline solution, one with an anaesthetic with 20 mg/mL of mepivacaine 2% and another syringe with a corticoid injection with 40 mg/mL of triamcinolone acetonide will be prepared before the intervention.12 The technique will be performed in aseptic conditions. First, the anaesthetic will be injected directed to the calcification. Then, the procedure will consist of injecting saline solution and aspiring the calcific deposits until it is neither possible to aspire more inside the syringe nor to detect any calcifications with ultrasound imaging. After that, a corticoid will be injected into the bursa to prevent the appearance of subacromial bursitis, which is one of the most common adverse effects following US-PICT.33 Finally, an anaesthetic will be injected during the extraction of the needle to prevent the spread of corticoid throughout the muscle to prevent atrophy. If the patient experiences anxiety before the intervention, the medical practitioner will administer an anxiolytic 20 min prior to the procedure, provided there is no medical contraindication (ie, allergy).
(Actual) wait-and-see group
The wait-and-see group will not receive any intervention and will serve as a control group to determine the natural history of RCCT.12 If one treatment proves to be more effective, participants in this group will be offered that treatment at no cost and under the same conditions after 12 months if their symptoms persist.
Data collection
Sociodemographic variables, including age, sex, height, weight, durations of symptoms, current work status, level of education, smoking, medication, comorbidities (hypertension, hypothyroidism, diabetes and dyslipidaemia) and body mass index will be measured at baseline assessment.
Additionally, at baseline assessment, patients will be given PROMs that will measure central sensitization, assessed with the Central Sensitization Inventory34; pain catastrophizing, with the Pain Catastrophizing Scale35; fear of movement, with the Tampa Scale for Kinesiophobia-1136; fear avoidance behaviour, with the Fear Avoidance Belief Questionnaire37; anxiety and depression, with the Hospital Anxiety and Depression Scale38; sleep quality with the Pittsburgh Sleep Quality Index39; and quality of life, with the EuroQol-5D.40
Outcomes
Primary and secondary outcomes (table 2) (except radiological variables) will be collected by the principal evaluator responsible for performing all the assessments who will be blinded to participants’ group allocation, data collection and analysis. A second researcher (radiologist) will collect the radiological variables and will be blinded to the intervention group.
Outcomes and assessment timepoints
Primary outcome
The primary outcome of this study will be shoulder pain measured with the Spanish version of the SPADI.41
Secondary outcomes
Secondary outcomes will include: patient satisfaction, measured with the Patient Global Impression of Change Scale42; worst pain and night pain, measured with a VAS43; shoulder ROM in flexion, abduction and hand behind the back, measured with an inclinometer44; and shoulder disability measured with the SPADI—Disability.41
Radiological variables including type of calcification according to the Gartner classification, location, size (by measuring the longest axis of the calcification) and number of calcifications3 will be collected by a radiologist, blinded to interventions, by using a standard anteroposterior radiograph view.3
Adverse events
Participants will be informed about the potential adverse events resulting from each intervention, including the measures they can take if that occurs. The ESWT group will be informed that they are likely to feel some pain or mild bruises on the area of application that resolve in less than a week.12 Meanwhile, the US-PICT group will be informed that this intervention could provoke subacromial bursitis, muscle atrophy and dizziness, but all of these adverse events are very unlikely (5%).12 33 All adverse events are written in the informed consent that each participant must complete prior to participate in the study. They will also be informed that they will be able to contact the main researcher to answer any question about these events. These adverse events have been reviewed and approved by the ethics committee (reference number: 1718862).
Sample size
The sample size was calculated based on the 95% CI width of the adjusted between-group mean difference at 1-year follow-up, from an analysis of covariance (ANCOVA) including baseline measurement as the covariate.45 The SPADI was selected as the primary outcome measure. We assumed an equal SD of 20 at 1-year follow-up,46 and a correlation of 0.50 between baseline and 1-year measurement.47 The adjusted mean difference was assumed to be 18 which is the value some authors have established as the minimum detectable change in SPADI.27 It was considered that a 95% CI width of 20 was acceptable because the lower bound is set at 8, which is the smallest value established in research as the minimum clinically important difference in SPADI.27 48 We transformed the CI width of non-adjusted difference to the ANCOVA adjusted one, using the formula proposed by previous authors,48 
, where r is the correlation between baseline and post-treatment measurement.48 The estimated sample size was 23 subjects per group (92 subjects in total). Assuming a 20% dropout rate at 1-year follow-up, the final sample size was composed of 29 subjects per group (116 subjects in total).
Data integrity and management
All data will be processed according to the Data Protection Act 2018 and will be stored safely in one storage device with restricted access (ie, only accessible to the researchers). All clinical outcomes recorded will be anonymized by giving each participant a random code number at the beginning of the study, which has nothing to do with personal information, to protect confidentiality. Participants who decide to cancel their participation in the study will be asked to provide reasons for their withdrawal, which will be reported.
Missing data will be reported and summarised based on the intervention groups. First, the reasons for missing data will be reported. Second, a logistic regression analysis will be conducted to evaluate if there is an association between baseline characteristics and missing data. Finally, an intention-to-treat approach will be employed to deal with missing data, using the worst-case and best-case scenario analysis, which is based on replacing any missing values with the best/worst estimate for their group at a given follow-up time. With this analysis, we can compare the obtained results with the expected results under the best-case scenario (in favour to the experimental group) or worst-case scenario (in favour to the control group), to assess if there are differences between those situations, in aim to discern the extent of impact of missing data and provide a better interpretation of the results.
Statistical analysis
Data distribution will be evaluated with visual inspection of density plots, Q–Q plots and kurtosis and skewness measures, as well as Shapiro-Wilk’s test. For the descriptive quantitative variables, mean and SD will be reported. For categorical data, absolute and relative frequencies will be reported.
For the analysis of between-group differences on quantitative outcome measures, mixed-model analyses of covariance (ANCOVA) will be conducted, with baseline measure as a covariate, group as between-subjects’ factor, and time as within-subjects’ factor. Post hoc pairwise comparisons will be conducted with adjusted between-group differences based on Student’s t-test with Bonferroni’s correction.49 In the case of ordinal outcome measures, a rank-based between-by-within analysis will be conducted, following the approach of Brunner et al.49 Post hoc pairwise comparisons will be conducted controlling familywise error rate using Rom’s method of the Benjamini-Hochberg method. Finally, if any quantitative variable does not accomplish the needed assumptions, robust analogous methods will be used instead.
Secondary moderation analyses will be conducted, evaluating the moderator effect of cognitive and quantitative sensory testing variables, on adjusted between-group differences of primary outcome measure at 12-month follow-up, using a multiple linear regression approach with a percentile bootstrap with 5000 samples. The effect size of the interactions will be evaluated with the change in the determination coefficient (R2) when including the interaction terms. Finally, for the interpretation of the results, the Johnson-Neyman technique for the evaluation of significance intervals will be employed.
All the analyses will be conducted using R software V.4.1.0.50 And a level of 0.05 with 95% CI will be assumed for all analyses. Reasons of missing data will be analysed and reported, and an intention-to-treat approach will be employed, using a worst-case and best-case scenario analysis.
Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Ethical approval and dissemination
This trial protocol has been reviewed and approved by the ethic committee of the University of Valencia, Spain (reference number: 1718862) (5 May 2022) and has been registered at https://clinicaltrials.gov, (NCT05478902). This clinical trial protocol has been elaborated following Standard Protocol Items: Recommendations for Interventional Trials checklist51 for clinical trial protocols. The clinical trial based on this protocol will be elaborated according to Consolidated Standards of Reporting Trials statement guideline for randomised clinical trials.52 The results of this study are planned to be published in a peer-reviewed journal.
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